The DOI matches its Crossref record; 27 of the 28 references it cites were found in a registry or an index.
Impaired Degradation of Mutant α-Synuclein by Chaperone-Mediated Autophagy
Abstract
Aberrant α-synuclein degradation is implicated in Parkinson's disease pathogenesis because the protein accumulates in the Lewy inclusion bodies associated with the disease. Little is known, however, about the pathways by which wild-type α-synuclein is normally degraded. We found that wild-type α-synuclein was selectively translocated into lysosomes for degradation by the chaperone-mediated autophagy pathway. The pathogenic A53T and A30P α-synuclein mutants bound to the receptor for this pathway on the lysosomal membrane, but appeared to act as uptake blockers, inhibiting both their own degradation and that of other substrates. These findings may underlie the toxic gain-of-function by the mutants.
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“Previous studies suggest that α-synuclein is degraded by macroautophagy, chaperone-mediated autophagy, and the proteasome20–23.”
From Microglia clear neuron-released α-synuclein via selective autophagy and prevent neurodegeneration (2020) · cites this paper as [20]
In the citing paper
“Finally, inhibition of a particular degradative pathway is typically accompanied by an increase in a separate pathway as the cell attempts to compensate for the loss of degradative capacity.158,478,493”
From Guidelines for the use and interpretation of assays for monitoring autophagy (2012) · cites this paper as [493]
In the citing paper
“and animal models with defective lysosomal exocytosis (VAMP7 mice) or defective lysosomal protease activity (Cathepsin D mutant mice) have mild to moderate demyelination.40–42”
From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [42]
In the citing paper
“dopamine-modified α-synuclein blocks chaperone-mediated autophagy [109,110], which induces abnormal intracellular accumulation α-synuclein in PD [120].”
From Degradation of Tyrosine Hydroxylase by the Ubiquitin-Proteasome System in the Pathogenesis of Parkinson’s Disease and Dopa-Responsive Dystonia (2020) · cites this paper as [109]
In the citing paper
“Early evidence suggested roles for CMA and macroautophagy in degrading SNCA/α‐synuclein (Webb et al, 2003; Cuervo et al, 2004).”
From Autophagy in major human diseases (2021) · cites this paper as Cuervo et al, 2004
In the citing paper
“High expression of wild‐type SNCA/α‐synuclein, mutations or unwanted posttranslational modifications on this protein (such as formation of dopamine adducts) is toxic to CMA by preventing multimerization of LAMP2A and subsequent lysosomal internalization of cargo proteins (Cuervo et al, 2004; Martinez‐Vicente et al, 2008).”
From Autophagy in major human diseases (2021) · cites this paper as Cuervo et al, 2004
In the citing paper
“The protein catabolic pathways that regulate synuclein degradation have been discussed by multiple authors4,16,17, and the extent to which autophagy contributes to synuclein degradation depends on the presence of mutations18.”
From Loss of autophagy in dopaminergic neurons causes Lewy pathology and motor dysfunction in aged mice (2018) · cites this paper as [18]
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BackgroundInhibition of lysosomal functions reduces proteasomal activity
Qiao, L., & Zhang, J. (2009) · Neuroscience Letters · doi:10.1016/j.neulet.2009.03.085 · Cited by 61
“Parkinson’s disease causing A53T and 30P mutant -synuclein, dopamine-modified or S129 phosphoylated -synuclein, blocks chaperone-mediated autophagy in the ell [36,12].”
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CDK5-mediated phosphorylation and autophagy of RKIP regulate neuronal death in Parkinson's disease
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“The studies of CMA in the nervous system have identified several significant protein characters as CMA substrates, including a-synuclein (Cuervo et al., 2004), tau (Wang et al.”
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“This can be attributed to the fact that a-syn can be degraded by the 20S proteasome in an ubiquitination-independent manner (Tofaris et al. 2001), or by the chaperone-mediated autophagy (Cuervo et al. 2004).”
BackgroundThe ubiquitin ligase E6‐AP promotes degradation of α‐synuclein
Mulherkar, S. A., Sharma, J., & Jana, N. R. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06293.x · Cited by 60
“This suggests that the degradation and refolding machinery is involved in these diseases. a-Synuclein is a substrate of proteasome and different mutations lead to an increase in its half-life and its subsequent accumulation in the cell (Bennett et al. 1999; Cuervo et al. 2004).”
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“Elevated α-synuclein levels are a consequence of alterations in the ubiquitin–proteasome system or the autophagy–lysosomal pathway that obstruct α-synuclein degradation (Cuervo et al., 2004; Webb et al., 2003).”
BackgroundThe LRRK2–macroautophagy axis and its relevance to Parkinson's disease
Manzoni, C. (2017) · Biochemical Society Transactions · doi:10.1042/bst20160265 · Cited by 57
“Mutated α -synuclein is known to impair chaperone-mediated autophagy (CMA) [16], and it is assumed that a change in the balance between its production and degradation rates may lead to its accumulation during PD. PD genome-wide association studies (PD-GWAS) suggested different candidate genes as…”
Centrality of Early Synaptopathy in Parkinson’s Disease
Imbriani, P., Schirinzi, T., Meringolo, M., Mercuri, N. B., & Pisani, A. (2018) · Frontiers in Neurology · doi:10.3389/fneur.2018.00103 · Cited by 59
Heterozygosity for a Mendelian disorder as a risk factor for complex disease
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Molecular insights into Parkinson's disease
Thomas, B., & Beal, M. F. (2011) · F1000 Medicine Reports · doi:10.3410/m3-7 · Cited by 62
“Finally, there is the suggestion that as mutant species of a-synuclein are poor substrates for proteasomal degradation, they inhibit proteolysis [27], block lysosomal function [28] (Figure 1) and chaperonemediated autophagy [29], and disrupt endoplasmic reticulum-Golgi trafficking [30,31], causing toxicity.”
BackgroundSynaptic dysfunction in genetic models of Parkinson's disease: A role for autophagy?
Plowey, E. D., & Chu, C. T. (2010) · Neurobiology of Disease · doi:10.1016/j.nbd.2010.10.011 · Cited by 62
“…proteins for lysosomal translocation by the LAMP2A receptor by cytosolic chaperone proteins, also contributes to α-synuclein degradation (Mak et al., 2010; Vogiatzi et al., 2008) and is impaired in models of synucleinopathy (Cuervo et al., 2004; Martinez-Vicente et al., 2008; Xilouri et al., 2009).”
Genetic analysis of the ATG7 gene promoter in sporadic Parkinson's disease
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Lysosomal trafficking defects link Parkinson's disease with Gaucher's disease
Wong, Y. C., & Krainc, D. (2016) · Movement Disorders · doi:10.1002/mds.26802 · Cited by 61
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BackgroundLysosomal function in macromolecular homeostasis and bioenergetics in Parkinson's disease
Schneider, L. E., & Zhang, J. (2010) · Molecular Neurodegeneration · doi:10.1186/1750-1326-5-14 · Cited by 59
“Chaperone-mediatedautophagy is initiated when chaperones bind to a consensus sequence in target proteins, and deliver them to the lysosomes via the chaperone-mediated-autophagy receptor, lysosomal-associated membrane protein 2a (LAMP-2a), which is a splice variant of LAMP-2 [127].”
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Implications of Selective Autophagy Dysfunction for ALS Pathology
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Catabolic Insufficiency and Aging
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Ahlskog, J. E. (2009) · Parkinsonism & Related Disorders · doi:10.1016/j.parkreldis.2009.09.010 · Cited by 59
“Thus, wild-type alpha-synuclein is predominantly degraded by chaperone-mediated autophagy, which is disrupted by pathogenic alpha-synuclein mutants [73,74].”
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Hamano, T., Hayashi, K., Shirafuji, N., & Nakamoto, Y. (2018) · Current Alzheimer Research · doi:10.2174/1567205015666181004143432 · Cited by 57
Intracellular alpha-synuclein affects early maturation of primary oligodendrocyte progenitor cells
Ettle, B., Reiprich, S., Deusser, J., Schlachetzki, J. C. M., Xiang, W., Prots, I., Masliah, E., Winner, B., Wegner, M., & Winkler, J. (2014) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2014.06.012 · Cited by 57
“…both the ubiquitin–proteasome system and the autophagy lysosome pathway with consecutive functional impairment of these protein degradation pathways was shown possibly contributing to the observed accumulation of PDGFRα protein (Cuervo et al., 2004; Snyder et al., 2003; Tanaka et al., 2001).”
BackgroundDeregulation of autophagy and vesicle trafficking in Parkinson’s disease
Sheehan, P., & Yue, Z. (2018) · Neuroscience Letters · doi:10.1016/j.neulet.2018.04.013 · Cited by 56
Non-small molecule PROTACs (NSM-PROTACs): Protein degradation kaleidoscope
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“…a-synuclein, DJ-1, parkin, PTEN-induced putative kinase 1, and Leucine-rich repeat kinase 2 are in part involved in the autophagy pathway (Cuervo et al. 2004; Plowey et al. 2008; Xilouri et al. 2009; Irrcher et al. 2010; Michiorri et al. 2010), suggesting that autophagy may be…”
BackgroundParkinson’s disease: From human genetics to clinical trials
van der Brug, M. P., Singleton, A., Gasser, T., & Lewis, P. A. (2015) · Science Translational Medicine · doi:10.1126/scitranslmed.aaa8280 · Cited by 57
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Dysregulated Interorganellar Crosstalk of Mitochondria in the Pathogenesis of Parkinson’s Disease
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Lysosomal Ion Channels: What Are They Good For and Are They Druggable Targets?
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Gollamudi, S., Johri, A., Calingasan, N. Y., Yang, L., Elemento, O., & Beal, M. F. (2012) · PLoS ONE · doi:10.1371/journal.pone.0036191 · Cited by 57
“Wild type and mutant a-synuclein are degraded by chaperone mediated autophagy (CMA) [55].”
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“…aggregates and organelles in the central nervous system (CNS; Wong and Cuervo, 2010), and it is affected in most diseases that show toxic accumulation of proteins, such as Alzheimer’s disease (AD; Pickford et al., 2008), PD (Cuervo et al., 2004; Crews et al., 2010) and DLB (Crews et al., 2010).”
BackgroundVesicle trafficking and lipid metabolism in synucleinopathy
Fanning, S., Selkoe, D. J., & Dettmer, U. (2020) · Acta Neuropathologica · doi:10.1007/s00401-020-02177-z · Cited by 56
TRIM44 links the UPS to SQSTM1/p62-dependent aggrephagy and removing misfolded proteins
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Cognitive heterogeneity in Parkinson’s disease: A mechanistic view
Carceles‐Cordon, M., Weintraub, D., & Chen‐Plotkin, A. S. (2023) · Neuron · doi:10.1016/j.neuron.2023.03.021 · Cited by 63
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Association between GBA L444P mutation and sporadic Parkinson's disease from Mainland China
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α-Synuclein overexpression increases dopamine toxicity in BE(2)-M17 cells
Bisaglia, M., Greggio, E., Maric, D., Miller, D. W., Cookson, M., & Bubacco, L. (2010) · BMC Neuroscience · doi:10.1186/1471-2202-11-41 · Cited by 57
“long-lived by chaperone mediated autophagy [36], an effect that can be seen with A30P a-synuclein without the incubation of the protein with DA [45].”
BackgroundProtein Transmission, Seeding and Degradation: Key Steps for α-Synuclein Prion-Like Propagation
Oueslati, A., Ximerakis, M., & Vekrellis, K. (2014) · Experimental Neurobiology · doi:10.5607/en.2014.23.4.324 · Cited by 58
“Although the exact mechanisms are still unclear, overall, it has been demonstrated that intracellular α-syn monomers and aggregates are predominantly degraded by the ubiquitin-proteasome system (UPS) [83-86] and the autophagy-lysosome pathway [85, 8789], including chaperone-mediated autophagy (CMA) [90, 91].”
BackgroundEnhanced Lysosomal Pathology Caused by β-Synuclein Mutants Linked to Dementia with Lewy Bodies
Wei, J., Fujita, M., Nakai, M., Waragai, M., Watabe, K., Akatsu, H., Rockenstein, E. M., Masliah, E., & Hashimoto, M. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m703711200 · Cited by 55
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Analysis of Chaperone-Mediated Autophagy
Juste, Y. R., & Cuervo, A. M. (2019) · Methods in molecular biology · doi:10.1007/978-1-4939-8873-0_47 · Cited by 55
Self-citationThe potential roles of deubiquitinating enzymes in brain diseases
Lim, K., Joo, J., & Baek, K. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101088 · Cited by 59
“In addition, the proteasome, as well as the lysosome, cannot degrade A53T mutated SNCA, and this leads to promotion of fibrilization (Cuervo et al., 2004).”
BackgroundTreating Parkinson’s Disease with Antibodies: Previous Studies and Future Directions
Castonguay, A.-M., Gravel, C., & Lévesque, M. (2020) · Journal of Parkinson s Disease · doi:10.3233/jpd-202221 · Cited by 55
Dysfunction of chaperone-mediated autophagy in human diseases
Liao, Z., Wang, B., Liu, W., Xu, Q., Hou, L., Song, J., Guo, Q., & Li, N. (2021) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-020-04006-z · Cited by 56
Gaucher Disease and the Synucleinopathies
Hruska, K. S., Göker-Alpan, Ö., & Sidransky, E. (2006) · BioMed Research International · doi:10.1155/jbb/2006/78549 · Cited by 54
Disease-Modifying Pathways in Neurodegeneration
Finkbeiner, S. M., Cuervo, A. M., Morimoto, R. I., & Muchowski, P. J. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.3829-06.2006 · Cited by 55
“We showed that mutant forms of -synuclein block CMA (Cuervo et al., 2004).”
BackgroundSelf-citationProtein aggregation, cardiovascular diseases, and exercise training: Where do we stand?
Gouveia, M., Xia, K., Colón, W., Vieira, S. I., & Ribeiro, F. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2017.07.005 · Cited by 54
Lizama, B. N., Kahle, J., Catalano, S. M., Caggiano, A. O., Grundman, M., & Hamby, M. E. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24076251 · Cited by 54
“Wildtype α-sy uclein has been shown to be selectively egr ded via chap ron -mediated utophagy [165].”
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van Dam, L., & Dansen, T. B. (2020) · Biochemical Society Transactions · doi:10.1042/bst20190054 · Cited by 56
Activated microglia facilitate the transmission of α-synuclein in Parkinson's disease
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Are heat shock proteins therapeutic target for Parkinson's disease?
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“It has been reported that Hsp70 is associated with αSN, dopamine transporter (DAT), parkin, proteasome subunits, ubiquitin and UCH-L1 [18].”
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Rho Kinase and Dopaminergic Degeneration: A Promising Therapeutic Target for Parkinson’s Disease
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“ATP13A2 is a lysosomal ATPase, and dysregulation of macroautophagy [16–18] and chaperone-mediated autophagy [19,20] has been shown in multiple models of dopaminergic neuronal injury.”
BackgroundModulation of Autophagy by Calcium Signalosome in Human Disease
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“α-syn contains a KFERQ-like motif and its CMA-mediated degradation is significantly reduced for α-syn constructs lacking the KFERQ-like motif, and by LAMP2A knockdown [152,156].”
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“For example, inhibition of the autophagocytosis pathway and lysosomal protein degradation has been suggested to play a role in -synuclein toxicity in Parkinson’s disease [47].”
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Fibrillar α-synuclein toxicity depends on functional lysosomes
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Genetic causes of Parkinson's disease and their links to autophagy regulation
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“a-Synuclein, encoded by SNCA, can be degraded in its native form by CMA [20].”
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Self-citationc-Abl Inhibitors Enable Insights into the Pathophysiology and Neuroprotection in Parkinson’s Disease
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Activating Autophagy as a Therapeutic Strategy for Parkinson’s Disease
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Neurons and Glia Interplay in α-Synucleinopathies
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Regulation of α-synuclein homeostasis and inflammasome activation by microglial autophagy
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Targeted Suppression of Chaperone-Mediated Autophagy by miR-320a Promotes α-Synuclein Aggregation
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“Almost all major known degradation pathways have been implicated in the degradation of α-synuclein [11,12], particularly, autophagy and proteasomal pathways are considered to play key roles in the process [13–15], in which both ubiquitin-proteasome system [16,17] and the autophagy-lysosomal pathway were confirmed to d…”
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“After the demonstration that chaperone-mediated autophagy (CMA) represents the main catabolic pathway for alpha-synuclein [1, 2], it has been postulated that dysfunctions of CMA, even more than ubiquitin-proteasome system (UPS) and macroautophagy, are involved in the pathogenesis of PD.”
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Metadata
- Authors
- Cuervo, A. M., Stefanis, L., Fredenburg, R., Lansbury, P. T., & Sulzer, D.
- Affiliations
- Department of Anatomy and Structural Biology, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
- Brigham and Women's Hospital (US)
- Venue
- Science
- Published
- 2004-08-27
- Volume
- 305
- Issue
- 5688
- Pages
- 1292-1295
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2068288454
- Cited by
- 2,024
- References
- 28
- Citations by year
- 2026: 64 · 2025: 77 · 2024: 102 · 2023: 71 · 2022: 107 · 2021: 114 · 2020: 128 · 2019: 114 · 2018: 117 · 2017: 101 · 2016: 95 · 2015: 92 · 2014: 93 · 2013: 108 · 2012: 119
- FWCI
- 34.33
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (AG-021904)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Keywords
- alpha-synuclein, chaperone-mediated autophagy, Parkinson's disease, lysosomal degradation, A53T mutant, Lewy bodies, gain-of-function toxicity, protein degradation pathways
- MeSH terms
- Animals, Autophagy, Cells, Cultured, Glyceraldehyde-3-Phosphate Dehydrogenases, Half-Life, Intracellular Membranes, Lysosomes, Male, Mutation, Nerve Tissue Proteins, Neurons, Protein Binding, Antigens, CD, PC12 Cells, Rats, Wistar, Molecular Chaperones, Amino Acid Motifs, Protein Transport, Mice, Rats, Synucleins, alpha-Synuclein, Lysosomal Membrane Proteins
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